The proposed research involves extensions of a multi-state model of Alzheimer's disease (AD) and ischemic heart disease (IHD). The model is designed to study the effects of the Apolipoprotein-E gene (APOE) on the risks of both diseases, but it can be adapted to study the effects of any fixed traits. The model has important practical and theoretical implications for both demography and epidemiology. The potential of the model has been demonstrated by fitting it to published data. The proposed research will apply the model to raw data from 40 clinical studies of the relationship between APOE and AD. These studies include 5939 cases of AD and 8746 controls. The proposal includes six applications and extensions of the model: 1) A study of sex differentials in the role of APOE in AD in populations of European origin. This will test hypotheses about the causes of the higher risk of AD among women and the reduced differential in AD risk by APOE genotype among women. 2) Use the model to project the number of cases of AD to the year 2030 by duration of disease and severity of symptoms. This will examine the potential impact of a) projected declines in IHD mortality, b) likely new treatments to slow the progression of AD, and c) likely new approaches to delaying the age at onset of AD. An important aspect of this will be to examine the impact of different assumptions about which APOE genotypes will benefit from future developments. 3) Produce a more efficient computer program to estimate the parameters of the model. The model is currently programmed in a spreadsheet program which cannot be expanded to compare more than two populations. 4) Examine differences in the effects of APOE on AD by race/ethnicity. Previous research suggests there are large differences in the relationship between APOE and AD whites, African-Americans, Hispanics, and Japanese. This research will test hypotheses about the likely differences in the etiology of AD that underlie these differences in the patterns of risk. 5) It is likely that during the next few years there will be major findings of other risk factors (especially genetic risk factors) for AD. This will complicate the process of comparing studies across populations and quantifying the importance of individual risk factors. The model of APOE and AD will be expanded to include additional risk factors.